Sleep onset is the transition from wakefulness into sleep. Sleep onset usually transits intonon-rapid eye movement sleep (NREM sleep) but under certain circumstances (e.g.narcolepsy) it is possible to transit from wakefulness directly intorapid eye movement sleep (REM sleep).
During the 1920s an obscure disorder that causedencephalitis and attacked the part of the brain that regulates sleep influenced Europe and North America. Although the virus that caused this disorder was never identified, the psychiatrist and neurologistConstantin von Economo decided to study this disease and identified a key component in the sleep-wake regulation. He identified the pathways that regulated wakefulness and sleep onset by studying the parts of the brain that were affected by the disease and the consequences it had on thecircadian rhythm. He stated that the pathways that regulated sleep onset are located between the brain stem and thebasal forebrain. His discoveries were not appreciated until the last two decades of the 20th century when the pathways of sleep were found to reside in the exact place that Constantin von Economo stated.[1]
Sleep electrophysiological measurements can be made by attaching electrodes to the scalp to measure the electroencephalogram (EEG) and to the chin to monitor muscle activity, recorded as the electromyogram (EMG). Electrodes attached around the eyes monitor eye movements, recorded as the electro-oculogram (EOG).[2]
Von Economo, in his studies, noticed that lesions in the connection between the midbrain and the diencephalon caused prolonged sleepiness and therefore proposed the idea of an ascending arousal system. During the past few decades major ascending pathways have been discovered with located neurons and respectiveneurotransmitters. This pathway divides into two branches: one that ascends to the thalamus and activates the thalamus relay neurons, and another one that activates neurons in the lateral part of thehypothalamus and thebasal forebrain, and throughout thecerebral cortex. This refers to the ascending reticular activating system (cfreticular formation). The cell group involved in the first pathway is anacetylcholine-producing cell group calledpedunculopontine andlaterodorsal tegmental nucleus. These neurons play a crucial role in bridging information in between the thalamus and the cerebral cortex. These neurons have high activation during wakefulness and duringREM sleep and a low activation duringNREM sleep. The second branch originates from monoaminorgenic neurons. These neurons are located in thelocus coeruleus, dorsal and medianraphe nuclei, ventral periaqueductal grey matter, andtuberomammillary nucleus. Each group produces a different neurotransmitter. The neurons in thelocus coeruleus producenoradrenaline, as fore the neurons in the dorsal and medianraphe nuclei, ventral periaqueductal grey matter, andtuberomammillary nucleus produce serotonin, dopamine and histamine respectively. They then project onto the hypothalamic peptidergic neurons, which contain melanin-concentrated hormones ororexin, and basal forebrain neurons which containGABA andacetylcholine. These neurons then project onto thecerebral cortex. It has also been discovered that lesions to this part of the brain cause prolonged sleep or may produce coma.[1][3][4][5]
Some light was thrown on the mechanisms on sleep onset by the discovery that lesions in thepreoptic area and anteriorhypothalamus lead toinsomnia while those in the posterior hypothalamus lead to sleepiness.[6][7] Further research has shown that the hypothalamic region calledventrolateral preoptic nucleus produces the inhibitory neurotransmitterGABA that inhibits the arousal system during sleep onset.[8]
Sleep onset is induced by sleep-promoting neurons, located in theventrolateral preoptic nucleus (VLPO). The sleep-promoting neurons are believed to projectGABA type A andgalanin, two known inhibitory neurotransmitters, to arousal-promoting neurons, such as histaminergic, serotonergic, orexinergic, noradrenergic, and cholinergic neurons (neurons mentioned above). Levels of acetylcholine, norepinephrine, serotonin, and histamine decrease with the onset of sleep, for they are all wakefulness promoting neurotransmitters.[2] Therefore, it is believed that the activation of sleep-promoting neurons causes the inhibition of arousal-promoting neurons, which leads to sleep. Evidence has shown that during the sleep-wake cycle, sleep-promoting neurons and the arousal-promoting neurons have reciprocal discharges, and that duringNREM sleep,GABA receptors increase in the arousal-promoting neurons. This had led some to believe that the increase ofGABA receptors in the arousal-promoting neurons is another pathway of inducing sleep.[1][3][4][5]
Adenosine is also known as the sleep promoting nucleoside neuromodulator. Astrocytes maintain a small stock of nutrients in the form of glycogen. In times of increased brain activity, such as during daytime, this glycogen is converted into fuel for neurons; thus, prolonged wakefulness causes a decrease in the level of glycogen in the brain. A fall in the level of glycogen causes an increase in the level of extracellular adenosine, which has an inhibitory effect in neural activity. This accumulation of adenosine serves as a sleep-promoting substance.[2]
The majority of sleep neurons are located in the ventrolateral preoptic area (vlPOA). These sleep neurons are silent until an individual shows a transition from waking to sleep.[9] The sleep neurons in the preoptic area receive inhibitory inputs from some of the same regions they inhibit, including the tubermammillary nucleus, raphe nuclei, and locus coeruleus.[10] Thus, they are inhibited by histamine, serotonin, and norepinepherine. This mutual inhibition may provide the basis for establishing periods of sleep and waking. A reciprocal inhibition also characterizes an electronic circuit known as the flip-flop. A flip-flop can assume one of two states, usually referred to as on or off. Thus, either the sleep neurons are active and inhibit the wakefulness neurons, or the wakefulness neurons are active and inhibit the sleep neurons, Because these regions are mutually inhibitory, it is impossible for neurons in both sets of regions to be active at the same time. This flip-flop, switching from one state to another quickly, can be unstable.[11]
The sleep cycle is normally defined in stages. When an individual first begins to sleep, stage 1 is entered, marked by the presence of some theta activity, which indicates that the firing of neurons in the neocortex is becoming more synchronized, as well as alpha wave activity (smooth electrical activity of 8–12 Hz recorded from the brain, generally associated with a state of relaxation). This stage is a transition between sleep and wakefulness. This stage is classified as non-REM sleep.[2]